A chemical byproduct, or metabolite, created as the body breaks down ketamine likely holds the secret to its rapid antidepressant action, National Institutes of Health (NIH) scientists and grantees have discovered.

The NIH study found that this metabolite singularly reversed depression-like behaviors in mice without triggering any of the anesthetic, dissociative, or addictive side effects associated with ketamine.

“This discovery fundamentally changes our understanding of how this rapid antidepressant mechanism works and holds promise for development of more robust and safer treatments,” said Carlos Zarate, M.D. of the NIH’s National Institute of Mental Health (NIMH), a study co-author and a pioneer of research using ketamine to treat depression.

“Now that we know that ketamine’s antidepressant actions in mice are due to a metabolite, not ketamine itself, the next steps are to confirm that it works similarly in humans, and determine if it can lead to improved therapeutics for patients,” explained Todd Gould, M.D., of the University of Maryland School of Medicine

In hopes of finding leads to a more practical treatment, the research team sought to pinpoint the exact mechanism by which ketamine relieves depression. Ketamine belongs to a class of drugs that block cellular receptors for glutamate, the brain’s chief excitatory chemical messenger. Until now, the prevailing view was that ketamine produced its antidepressant effects by blocking N-methyl-D-aspartic acid (NMDA) glutamate receptors.

However, human trials of other NMDA-receptor blockers failed to produce ketamine’s robust and sustained antidepressant effects. So the team explored the effects of ketamine on antidepressant-responsive behaviors in mice.To find out, the researchers chemically blocked the metabolism of ketamine. This prevented formation of the metabolite, which blocked the drug’s antidepressant-like effects.

Ketamine also has effects in mice that mimic its dissociative, euphoric effects in humans and underlie its abuse and addictive potential; however, these effects were not observed with (2R,6R)-HNK. (2R,6R)-HNK did not cause the changes in physical activity, sensory processing, and coordination in mice that occur with ketamine. In an experimental situation where mice were able to self-administer medication, they did so with ketamine but not the (2R,6R)-HNK metabolite, indicating that (2R, 6R)-HNK is not addictive.

“Pending confirmation in humans, this line of studies exemplifies the power of mouse translational experiments for teasing out brain mechanisms that hold promise for future treatment breakthroughs,” added NIMH acting director Bruce Cuthbert, Ph.D.

The researchers are now following up on their discovery with safety and toxicity studies of the metabolite as part of a drug development plan in advance of a NIMH clinical trial in humans for the treatment of depression.